The Slack gene encodes potassium channels that are abundantly expressed in the central nervous system. These channels are regulated by changes in the intracellular sodium ion concentration. The rapid influx of sodium ions through sodium channels or neurotransmitter receptors results in a sodium-sensitive potassium current (IKNa). Alterations in IKNa due to mutations in Slack channels cause several early onset epileptic encephalopathies. Additionally, epilepsies associated with mutations in Slack channels are associated with a severe delay in cognitive development. The large cytoplasmic C-terminal tail of Slack channel interacts primarily with a protein termed Phactr-1 (Phosphatase and Actin regulator-1) and with the Fragile-X Mental Retardation protein (FMRP). In this proposal, I plan to study how disease-causing mutations modify the association of Slack channels with these binding partners, and how these interactions are linked to changes in neuronal protein translation. The outcome of this study will contribute to our understanding of the regulation of Slack channel activity, and is likely to lead to potential therapies for the devastating condition produced by Slack mutations.

Public Health Relevance

Malfunction of the Na+-activated K+ channel (Slack) has been implicated in epilepsy and intellectual disability. This proposal focuses on understanding the molecular mechanism of Slack channels and its interaction with other binding proteins. The new knowledge gained from this study may be useful for the treatment of Slack channels-related brain disorders such as epilepsy and intellectual disability. .

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HD093292-01
Application #
9394578
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Krotoski, Danuta
Project Start
2017-09-01
Project End
2020-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ali, Syed R; Liu, Zhiqing; Nenov, Miroslav N et al. (2018) Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic. ACS Chem Neurosci 9:976-987